Preconceptional immunity to HCMV does not fully protect against maternal reinfection with heterologous strains of virus and transplacental transmission of virus to the fetus. In addition, the frequency of fetal sequelae following either reactivation or reinfection of the mother may be greater than once generally believed. These findings highlight that our understanding of both the correlates of protective immunity to HCMV and HCMV natural history are incomplete. Resolution of these issues is paramount to design effective vaccine strategies. Maternal immune responses to HCMV infection can be considered protective because clinical outcomes in the mother are rare. Antiviral immune responses are not protective in that HCMV can disseminate in the presence of antiviral immunity. Reactivated virus can potentially be transmitted horizontally and/or vertically across the placenta. It is the inability of antiviral immunity to restrict HCMV replication that defines the limitation of the immune response. Vaccine strategies may need to be extended to include some seropositive individuals to achieve two potential goals. One goal would be to reduce pathological outcomes of endogenously or exogenously acquired virus. The other would be a reduction in the frequency of HCMV reactivation. HYPOTHESIS: Immunization of HCMV seropositive hosts against HCMV antigens can reduce both the frequency and titer of reactivated virus. This hypothesis will be tested in the rhesus macaque model. We have observed that some macaques are consistently negative for rhesus CMV (RhCMV) DNA in mucosal swabs. In contrast, swabs from other animals are persistently positive for RhCMV DNA. The following Aims will test whether immunization of RhCMV DNA-positive monkeys reduces RhCMV load in mucosal fluids. (1) Longitudinal screening of seropositive animals for rates and titers of RhCMV DNA in mucosal fluids. (2) Genetic immunization of animals with plasmid expression vectors for RhCMV antigens or control plasmids. (3) Post-immunization assessment of RhCMV detection frequency and titer.